Author: gdotto

Breast cancer strikes one out of eight women in Switzerland. A woman’s risk to get breast cancer is linked to her reproductive history. While early pregnancies have a protective effect, cancer risk increases with the number of menstrual cycles a woman experiences prior to her first pregnancy. Although it is well established that the female sex hormones estrogen, progesterone and prolactin control breast development and have an important role in breast carcinogenesis, the mechanisms by which they exert their effects are poorly understood.

A main research goal at ICPI is to understand how hormones interact with developmental signaling pathways in the breast to control growth and differentiation and how they contribute to breast cancer development. The aim is to translate the insights into novel approaches for breast cancer prevention at the primary human population level (i.e. for pre- and post-menopausal women, contraception and hormone replacement therapies) as well as at the secondary and tertiary level (i.e. personalised approaches to prevent breast cancer progression and relapse ).

Switzerland is among the countries with the highest incidence of melanoma in the world, with the rate of this deadly disease constantly increasing. Significant advances have been made over the last few years in melanoma treatment. Despite initial dramatic response to drugs designed to target specific activated molecules in these tumours, the clinical benefit is very often transient, due to rapid development of resistance. More recently, alternative therapy approaches based on activation of the immune system can be very successful, but unfortunately in only 20-25% of patients. Together with the persisting need for improved treatment, there is an urgency to devise more effective ways to prevent melanoma development, for treatment of premalignant melanotic lesions and suppression of “secondary melanomas” that can appear after removal of the primary tumour.

The incidence of many cancer types in organs with non-reproductive functions, including melanoma, is significantly higher in the male than female populations, with a lower survival. A better appreciation of the differences between the two sexes can be of substantial value for both melanoma prevention and treatment. Current efforts of ICPI, in the Dotto’s laboratory in collaboration with oncologist Berna Ozdemir, are focused on investigating the interplay between sex hormones and chromosomes in the early steps of melanoma development and how this knowledge can be used for novel pharmacological approaches of clinical significance.

Cancers do not arise solely from a single deregulated group of cells but rather as a combined result of various alterations in organ and tissue homeostasis. In fact, many genetic changes found in invasive and metastatic tumors are also found in apparently normal tissues and, for reasons that are not yet understood, only a minor fraction of pre-malignant lesions progress to malignancy.

A main research focus at ICPI is on biological determinants of pre-malignant to malignant skin tumor conversion and on field cancerization, a process of major clinical significance that consists of multifocal and recurrent tumors that are associated with widespread changes of surrounding normal tissues (Dotto, 2014).

A main researThe 3 main types of skin cancer, basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma have a major impact on human health, with skin BCC and SCC being by far the most common type of human cancer worldwide, and melanoma being among the most aggressive. While SCCs and melanomas are preceded and accompanied by premalignant lesions, BCCs appear without discernible precursors but also frequently appear as multiple or recurrent lesions.

Skin field cancerization is a major clinical problem for sun-exposed ageing human populations of caucasian origin and for organ transplant recipient patients under treatment with immune suppressants to prevent rejection.

While previous research on field cancerization has focused on changes in cancer cells of origin as primary drivers, work at ICPI has pioneered studies on the initiating role that stromal fibroblast alterations can also play in the whole process, with modulation of androgen receptor expression and activity as a key player (Clocchiatti et al., 2018).

Overall, a complex interplay involves differences in sex hormones levels and activity in the mesenchymal versus epithelial compartment of the skin, as a function of sex, age, and UV sun exposure. Insights into underlying cellular and molecular mechanisms are of likely translational significance for devising novel approaches for primary, secondary and tertiary cancer prevention targeting the epigenome.