Periodic Reporting for period 2 - CANCERPREV (Innovative strategies for cancer prevention with focus on sex hormone signaling and chronic inflammation)
Reporting period: 2021-11-01 to 2024-02-29
Worldwide, the number of people affected by cancer grows (WHO Feb 2024) and more than 35 million cases are predicted in 2050. This is largely explained by (i) increased life span, (ii) improved early disease detection, (iii) longer survival of cancer patients in developed countries, and (iv) changes in exposures to risk factors linked to socioeconomic development, including addictions: tobacco, alcohol, obesity, and air pollution. Expensive cancer treatments cannot be afforded by all societies, and even health care systems in "rich countries" stumble over prices for new therapies. Complex cancer evolution prohibits durable clinical treatment of advanced-stage tumors.
Current research efforts largely focus on mechanisms of tumor growth and spread with the aim to identify more effective treatments. Less attention is paid to study how, in whom and when to prevent the disease because it is difficult to measure success in cancer prevention; it demands a longer-term vision and a shift in resources. Hence, a focus on cancer prevention and on behavioral and societal factors that underpin common risk factors is timely and urgent.
We have trained young scientists in interdisciplinary approaches to address these challenges. Collaboratively, we have revealed how inflammation and hormones can accelerate or slow the development of tumors in the skin and breast. We focused on the role of sex hormones and chronic inflammation, individually and in combination, on breast and skin cancer development. Both contribute to significant differences in cancer risk between males and females with important clinical implications. To ensure that patients diagnosed at early stages are not under- or over-treated, we bridged molecular biology research with statistical tools. This has led to new blood tests and computational tools that will help clinicians determine the risk of patients’ cancers progressing. Finally, we identified familial genetic and behavioral risk factors, matched to drug- based and more societal approaches, such as smoking cessation support, that can be adapted to stop tumor growth in individual patients. Excitingly, by analyzing rates of cancer development in identical twins we have shown that stress affects the recurrence of breast cancer.
Importantly, we promoted the scientific communication skills of ESRs, through participation in outreach efforts towards the general public, establishment of vibrant social media platforms on cancer prevention, broad audience meetings and more focused informational gatherings dedicated to the topic. These activities will be continued and expanded through the institutions and private organizations that participated in our network.
Current research efforts largely focus on mechanisms of tumor growth and spread with the aim to identify more effective treatments. Less attention is paid to study how, in whom and when to prevent the disease because it is difficult to measure success in cancer prevention; it demands a longer-term vision and a shift in resources. Hence, a focus on cancer prevention and on behavioral and societal factors that underpin common risk factors is timely and urgent.
We have trained young scientists in interdisciplinary approaches to address these challenges. Collaboratively, we have revealed how inflammation and hormones can accelerate or slow the development of tumors in the skin and breast. We focused on the role of sex hormones and chronic inflammation, individually and in combination, on breast and skin cancer development. Both contribute to significant differences in cancer risk between males and females with important clinical implications. To ensure that patients diagnosed at early stages are not under- or over-treated, we bridged molecular biology research with statistical tools. This has led to new blood tests and computational tools that will help clinicians determine the risk of patients’ cancers progressing. Finally, we identified familial genetic and behavioral risk factors, matched to drug- based and more societal approaches, such as smoking cessation support, that can be adapted to stop tumor growth in individual patients. Excitingly, by analyzing rates of cancer development in identical twins we have shown that stress affects the recurrence of breast cancer.
Importantly, we promoted the scientific communication skills of ESRs, through participation in outreach efforts towards the general public, establishment of vibrant social media platforms on cancer prevention, broad audience meetings and more focused informational gatherings dedicated to the topic. These activities will be continued and expanded through the institutions and private organizations that participated in our network.
The ESRs were trained in all aspects of cancer prevention with a focus on hormones and inflammation in skin and breast cancer. They acquired experimental and computational skills to address research questions and were provided courses and opportunities to develop their presentation and communication skills. Through secondments, they experienced different work environments, acquired additional skills and expanded their networks. They have built strong ties among each other and become cancer prevention ambassadors.
Our research efforts were hypothesis- and discovery-driven and went beyond the state-of-the art as follows:
1. Use of cutting-edge disease models:
• To study the effects of hormones on breast cancer risk, we used innovative models based on patient-derived tissues and cells, and hence highly clinically relevant.
• To study the effects of inflammation and dissect the importance of distinct factors on the development of skin cancer, we used carefully-defined novel genetically-modified mice (ESR7-10).
2. Original and complementary approaches:
In addition to experimental approaches, we developed and used computational tools and made use of data from large Nordic twin cohorts and large sets of patient blood samples collected along with clinical information from breast cancer and melanoma patients.
3. Team Science:
The project involved epidemiologists, bioinformaticians and mathematicians with access to a wealth of historic genetic and behavioral aspects of lifestyle data. Hypotheses were generated and tested mechanistically in preclinical models by the cancer biologists, who generated mechanistic insights and hypotheses of potential clinical significance, testable by transdisciplinary approaches.
Our scientific cross-talk also involved companies in the private health sector, health teaching, foundations, and leading pharmaceutical and technology companies who participated in training individual ESRs. This fostered the social impact and entrepreneurial spirit of the ESRs and generated important opportunities for future collaborations.
Our work has yielded new insights into how the body’s own reproductive hormones as well as synthetic hormones taken in the context of contraception or hormone replacement therapy may affect cancer risk and progression. Of public health relevance, some breast cancers can be prevented if the pill is chosen more carefully. All pills contain a progestin and there are different types. We have shown that androgenic progestins like levonorgestrol stimulate breast cell growth more than antiandrogenic progestins. The latter should hence be safer to use considering cancer risk.
Our studies identified striking differences between males and females with regards to biomarkers. Surprisingly, male melanoma patients showed many more differences among themselves than female patients. This implies that attention needs to be paid to a patient’s gender in developing blood tests to detect early disease or determine risk.
We have gained more insights into the role of acute and chronic inflammation on tumor development. In light of the obesity epidemic, which contributes to increased cancer incidence and creates an inflammatory state in affected patients, this is an ever more important area to research.
Ongoing work on the twin studies shows that stressful events may trigger breast cancer recurrence by leaving a mark in terms of chemical modification of the DNA with methyl groups. This is exciting as 80% of breast cancer patients have hormone sensitive disease. These cancers are slow growing but can recur after many years, a phenomenon called dormancy that remains poorly understood. Building on this work, it may be possible to identify patients at risk of recurrence by DNA marks and develop preventative measures for them.
Finally, innovative topological and other computational data analysis tools were developed that enhance the analytical power and enable researchers to explore new hypotheses and directions. The advent of large-scale population and patient data collection, linked to deeply annotated registries and biobanks provides unprecedented research opportunities that need to be seized to benefit society.
Addressing the sex hormone-dependent impact on cancer prevention, exploring the interconnection between sex differences and the inflammatory/immune systems, and integrating sex and gender analyses across all its research and innovation activities, the joint research effort by all beneficiaries and ESRs has created a more comprehensive approach - where previously the views were narrower.
As such, our innovative research and training network established a unique paradigm for advanced research, education and career development in cancer prevention.
1. Use of cutting-edge disease models:
• To study the effects of hormones on breast cancer risk, we used innovative models based on patient-derived tissues and cells, and hence highly clinically relevant.
• To study the effects of inflammation and dissect the importance of distinct factors on the development of skin cancer, we used carefully-defined novel genetically-modified mice (ESR7-10).
2. Original and complementary approaches:
In addition to experimental approaches, we developed and used computational tools and made use of data from large Nordic twin cohorts and large sets of patient blood samples collected along with clinical information from breast cancer and melanoma patients.
3. Team Science:
The project involved epidemiologists, bioinformaticians and mathematicians with access to a wealth of historic genetic and behavioral aspects of lifestyle data. Hypotheses were generated and tested mechanistically in preclinical models by the cancer biologists, who generated mechanistic insights and hypotheses of potential clinical significance, testable by transdisciplinary approaches.
Our scientific cross-talk also involved companies in the private health sector, health teaching, foundations, and leading pharmaceutical and technology companies who participated in training individual ESRs. This fostered the social impact and entrepreneurial spirit of the ESRs and generated important opportunities for future collaborations.
Our work has yielded new insights into how the body’s own reproductive hormones as well as synthetic hormones taken in the context of contraception or hormone replacement therapy may affect cancer risk and progression. Of public health relevance, some breast cancers can be prevented if the pill is chosen more carefully. All pills contain a progestin and there are different types. We have shown that androgenic progestins like levonorgestrol stimulate breast cell growth more than antiandrogenic progestins. The latter should hence be safer to use considering cancer risk.
Our studies identified striking differences between males and females with regards to biomarkers. Surprisingly, male melanoma patients showed many more differences among themselves than female patients. This implies that attention needs to be paid to a patient’s gender in developing blood tests to detect early disease or determine risk.
We have gained more insights into the role of acute and chronic inflammation on tumor development. In light of the obesity epidemic, which contributes to increased cancer incidence and creates an inflammatory state in affected patients, this is an ever more important area to research.
Ongoing work on the twin studies shows that stressful events may trigger breast cancer recurrence by leaving a mark in terms of chemical modification of the DNA with methyl groups. This is exciting as 80% of breast cancer patients have hormone sensitive disease. These cancers are slow growing but can recur after many years, a phenomenon called dormancy that remains poorly understood. Building on this work, it may be possible to identify patients at risk of recurrence by DNA marks and develop preventative measures for them.
Finally, innovative topological and other computational data analysis tools were developed that enhance the analytical power and enable researchers to explore new hypotheses and directions. The advent of large-scale population and patient data collection, linked to deeply annotated registries and biobanks provides unprecedented research opportunities that need to be seized to benefit society.
Addressing the sex hormone-dependent impact on cancer prevention, exploring the interconnection between sex differences and the inflammatory/immune systems, and integrating sex and gender analyses across all its research and innovation activities, the joint research effort by all beneficiaries and ESRs has created a more comprehensive approach - where previously the views were narrower.
As such, our innovative research and training network established a unique paradigm for advanced research, education and career development in cancer prevention.